Steven Mittelman, MD, PhD Lab

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Leukemia cells (yellow, GFP) are found in the fat tissue of a transplanted obese mouse that developed leukemia despite chemotherapy treatment. Fat cells are stained red (Nile red), and the nuclei of live cells are stained blue (DAPI). Image was taken on a Leica DM RXA2 (32X final magnification). Adapted from Behan et al., Cancer Research, 69: 7867-7874, 2009



RESEARCH TOPICS

  • Obesity and cancer in children

  • Adipose tissue inflammation

  • Appetite regulation


RESEARCH OVERVIEW

Obesity can cause a number of negative health effects. One of these effects is that being obese increases the risk of cancer and makes cancer harder to cure. We are trying to figure out the mechanisms responsible for obesity interacting with cancer.

Leukemia is the most common type of cancer in children. Researchers in The Saban Research Institute at Children’s Hospital Los Angeles discovered that children who were obese at the time they were diagnosed with the most common type of childhood leukemia have about a 50% higher chance of their disease coming back after treatment than patients who were lean. In our laboratory, we are looking into ways in which fat tissue might interact with leukemia cells, making the disease harder to cure. We are investigating how fat tissue:

  • Attracts leukemia cells to migrate closer to fat cells.
  • Absorbs some chemotherapy drugs, making them unable to reach the leukemia cells.
  • Produces fuels such as amino acids and fatty acids that help leukemia cells survive.
  • Secretes substances that signal the leukemia cells, making them more able to resist chemotherapy.

Bone marrow from leukemia patient

 

We are also studying how body weight, and other nutritional factors like vitamin D, might impact patients with leukemia both before and after treatment.

As obesity develops, immune cells infiltrate fat tissue, causing inflammation. This inflammation may be partly responsible for the development of diabetes, heart disease and cancer. We are looking into the communications between adipocytes, lymphocytes and macrophages, and how this might lead to insulin resistance and diabetes.


 

Accomplishments

  • We were the first to demonstrate that fat cells protect leukemia cells from a variety of chemotherapies.
  • We demonstrated, in two different models, that obesity directly accelerates leukemia progression.
  • We have found that macrophage infiltration of adipose tissue in obesity does not require lymphocytes.


Goals

  • To unravel the mechanisms responsible for obesity both increasing the chance of getting leukemia and decreasing the chance of surviving leukemia.
  • To develop strategies to block these effects of obesity on cancer.
  • To use our understanding of body weight regulation to improve the lives of patients with leukemia and other cancers.


Teaching

  • Fellowship Director for the Center for Endocrinology, Diabetes & Metabolism since 2006.
  • Director of the Donnell Society for Pediatric Scientists, which is dedicated to improving the health of children by training pediatric scientists to perform innovative and high-quality research


Current Funding

  • NIH/NCI R01: Investigating the Role of Adipocytes on Leukemia Relapse (PI: Mittelman)
    This grant supports our investigations into how obesity can affect the dosing of chemotherapy drugs such as vincristine and dexamethasone. It also supports our work to understand how fat cells can directly protect leukemia cells from chemotherapy.

  • Gabrielle’s Angel Foundation: Overcoming L-Asparaginase-Resistance Caused by Adipocyte Production of Glutamine (PI: Mittelman).
    This grant supports our studies on how fat cells produce amino acids which fuel leukemia cells and allow them to survive the chemotherapy, L-Asparaginase.

  • Leukemia & Lymphoma Society Translational Research Project: Vitamin D, Fat, and Development of Bone Abnormalities in ALL (PI: Mittelman)
    This grant funds a double-blind, placebo-controlled study of vitamin D and calcium supplementation in children with acute lymphoblastic leukemia.

  • The V Foundation Translational Grant:  Improving treatment outcome in leukemia by disruption of bone marrow-leukemia interactions relevant to minimal residual disease (PI: Heisterkamp).
    The purpose of this grant is to inhibit molecular pathways leading to leukemia migration into and adhesion within the bone marrow, to test whether this will improve leukemia outcome.

  • The Saban Research Institute 2nd R01 Pilot Award: The Role of Lymphocytes in Obesity-Induced Adipose Tissue Inflammation and Diabetes (PI: Mittelman).
    The aim of this grant is to investigate the role of lymphocyte subsets in the accumulation and activation of adipose tissue macrophages, using novel immunodeficient mouse models.

  • In addition to the above awards, our laboratory is grateful for the funding we receive from: The Bogart Cancer Research Program, the T.J. Martell Foundation and The Saban Research Institute.


Publications

Journal Articles

  • EA Ehsanipour, X Sheng, JW Behan, X Wang, A Butturini, VI Avramis, SD Mittelman
    Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase via Release of Glutamine
    Cancer Research, In Press

  • JW Behan, EA Ehsanipour, R Pramanik, X Sheng, Y-M Kim, Y-T Hsieh, SD Mittelman
    Activation of Adipose Tissue Macrophages in Obese Mice does not Require Lymphocytes
    Obesity, In Press (DOI: 10.1002/oby.20159)

  • R Pramanik1, X Sheng1, B Ichihara, N Heisterkamp, SD Mittelman
    Adipose tissue attracts and protects acute lymphoblastic leukemia cells from chemotherapy
    Leukemia Research, 37:503-9, 2013
    1co-first authors

  • DJ Lesser, R. Bhatia, WH Tran, F. Oliveira, R Ortega, TG Keens, SD Mittelman, MCK Khoo, SL Davidson Ward
    Sleep Fragmentation and Intermittent Hypoxemia Associated with Decreased Insulin
    Sensitivity in Obese Adolescent Latino Males
    Pediatric Research, 72:293-8, 2012

  • R Antony, X Sheng, EA Ehsanipour, E Ng, R Pramanik, L Klemm, B Ichihara, SD Mittelman
    Vitamin D Protects Acute Lymphoblastic Leukemia Cells from Dexamethasone
    Leukemia Research, 36:591-93, 2012

  • LJ Noetzli, A Panigrahy, SD Mittelman, A Hyderi, A Dongelyan, TD Coates, JC Wood
    Pituitary iron and volume predict hypogonadism in transfusional iron overload
    American Journal Of Hematology, 87:167-71, 2012

  • LJ Noetzli, SD Mittelman, RM Watanabe, TD Coates, JC Wood
    Pancreatic iron and glucose dysregulation in thalassemia major
    American Journal Of Hematology, 87:155-60, 2012

  • CM Southern Reh, SD Mittelman, C-P Wee, AC Shah, FR Kaufman, JR Wood
    A Longitudinal Assessment of Lipids in Youth with Type 1 Diabetes
    Pediatric Diabetes, 12:365-71, 2011

  • SA Chung, F Dorey, SD Mittelman, V Gilsanz
    Effect of Gender on Intra-abdominal Fat in Teenagers and Young Adults
    Pediatric Radiology, 41:469-75, 2011

Books, Chapters, Articles

  • SD Mittelman and A Butturini. Mechanisms Linking Obesity and Leukemia Prognosis. In: SD Mittelman and NA Berger (Eds.) Energy Balance and Hematologic Malignancies (pp. 47-69), New York, NY, Springer Science and Business Media, LLC, 2012

  • SD Mittelman and NA Berger (Eds.) Energy Balance and Hematologic Malignancies, New York, NY: Springer Science and Business Media, LLC, 2012 

  • Mittelman, Steve, Too Few Realize Obesity Can Cause Cancer

CONTACT US

Mittelman Lab
The Saban Research Institute
4650 Sunset Boulevard MS #93
Los Angeles, CA  90027
Email: Steven Mittelman, MD, PhD

323-361-4589

PRINCIPAL INVESTIGATOR

Steven Mittelman, MD, PhD
Steven Mittelman, MD, PhD

PubMed Link

Endocrinology, Diabetes & Metabolism

George Donnell Society

Curriculum Vitae 

LAB MEMBERS

GRADUATE STUDENTS

  • Ehsan Ehsanipour
  • Xia (Susan) Sheng
  • Jonathan Tucci

PEDIATRIC SUBSPECIALTY FELLOWS

RESEARCH SCIENTIST

  • Jean Hugues Parmentier, PhD

VOLUNTEERS

  • Teresa Herrera
  • Michelle Leisner
  • Onyekachim Okpo

COLLABORATIONS